Studies of the neuropathology of schizophrenia have documented a multitude of structural and functional brain abnormalities. The scope of these findings has been vast, and no single set of abnormalities has emerged as being characteristic of, or pathognomonic for, the disorder. However, a few specific themes have received enough empirical support to stand as potential models of the illness, and to offer testable hypotheses of the underlying pathophysiological mechanisms. Among the more robust of these are failures of appropriate neuronal inhibition & excitation and disturbed connectivity across cortical regions. Tests of these mechanisms in patients are limited by the practical constraints of in vivo clinical research and are, therefore, necessarily indirect and inferential. Recent developments in the use of transcranial magnetic stimulation (TMS) as a neurophysiological probe of cortical activity have suggested a means to test the functional integrity and responsivity of neural circuits in a more direct manner. By combining TMS with simultaneous multi-channel evoked potential (EP) recording, we believe that we can assess cortical inhibitory and facilitative mechanisms within localized brain areas, and the neural connectivity across brain regions. This is a novel methodology that has only been applied to a limited extent in the study of healthy individuals. It has been applied even less to the study of clinical populations. Early results, though, have been very promising, and further investigation of its applicability to the study of schizophrenia is clearly warranted. The goal of this project, therefore, is to establish the feasibility and utility of this methodology in the study of schizophrenia. Three experiments will be conducted, each in a sample of 16 schizophrenia patients and 16 healthy subjects. Experiment 1 will characterize the cortical evoked potential response to TMS stimulation, using a broad range of TMS pulse intensities. Experiment 2 will characterize intracortical inhibitory and facilitative mechanisms, using a paired- pulse design in which a suprathreshold TMS pulse is preceded by a subthreshold pulse at various inter-pulse intervals. Experiment 3 will assess regional differences in both the underlying TMS-evoked potential response, and the intracortical facilitation and inhibition of this response through single pulse and paired pulse stimulation of left and right frontal and temporal cortices. Patient-control differences in amplitude, latency and inter-cortical connectivity of the TMS-evoked response will be examined for all three experiments. PUBLIC HEALTH RELEVANCE Despite intensive investigation, the pathophysiology underlying schizophrenia remains unclear. This study will examine the utility of a novel methodology that combines transcranial magnetic stimulation with evoked potential response recording, to investigate the neural mechanisms of cortical inhibition, facilitation and connectivity in schizophrenia patients. This may help to clarify our understanding of the neuropathology of this debilitating disorder. [unreadable] [unreadable] [unreadable]